1. Field of the Invention
The present invention is directed to novel compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to 4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-benzoic and 2-[4-[(8-ethynyl, 8-vinyl or 8-ethynyl-methyl)-6-chromanoyl]-phenyl]-acetic acid, their esters and salts which inhibit either the enzyme cytochrome P450RAI1 or the enzyme cytochrome P450RAI2, or both enzymes.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
Several compounds having retinoid-like activity are actually marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation of gene expression, tissue differentiation and other important biological processes in mammals including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible). In fact, in the present state of the art it is known that at least two sub-species of cytochrome P450RAI enzymes exist, and these are termed P450RAI1 and P450RAI2. White et al. Identification of the human cytochrome P450), P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all trans retinoic acid metabolism, Proc. Natl. Acad. Sci. USA Volume 97 No. 12 pp6403-6408 (Jun. 6, 2000).
Several inhibitors of cytochrome P450RAI have been synthesized or discovered in the prior art,including the well known ketoconazole, liarozole and R116010 compounds. The chemical structures of these prior art compounds are provided below. Relatively recently issued U.S. Pat. No. 6,313,107 describes a number of compounds having cytochrome P450RAI inhibitory activity, and several compounds of this disclosure are substituted chroman derivatives.
It has also been noted in the prior art, that administration to mammals, including humans, of certain inhibitors of CP-450RAI results in significant increase in endogeneous RA levels, and further that treatment with CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis. 
The following publications describe or relate to the above-summarized role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI and to in vitro and in vivo experiments which demonstrate that inhibition of CP450RAI activity results in a increases indogeneous RA levels and potential therapeutic benefits:
Kuijpers, et al., xe2x80x9cThe effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretinxe2x80x9d, British Journal of Dermatology, (1998) 139: pp 380-389.
Kang, et al., xe2x80x9cLiarozole Inhibits Human Epidermal Retinoid Acid 4-Hydroxylase Activity and Differentially Augments Human Skin Responses to Retinoic Acid and Retinol In Vivoxe2x80x9d, The Journal of Investigative Dermatology, (August 1996) Vol.107, No. 2: pp 183-187.
Vorn Wauwe, et al., xe2x80x9cLiarozole, an Inhibitor of Retinoic Acid Metabolism, Exerts Retinoid-Mimetic Effects in Vivoxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.
De Porre, et al., xe2x80x9cSecond Generation Retinoic Acid Metabolism Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male Volunteersxe2x80x9d, University of Leuven, Belgium, pp 30.
Wauwe, et al., xe2x80x9cKetoconazole Inhibits the in Vitro and in Vivo Metabolism of All-Trans-Retinoic Acidxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.
White, et al., xe2x80x9ccDNA Cloning of Human Retinoic Acid-metabolizing Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*xe2x80x9d, The Journal of Biological Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.
Hanzlik, et al., xe2x80x9cCyclopropylamines as Suicide Substrates for Cytochromes P450RAIxe2x80x9d, Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-761.
Ortiz de Montellano, xe2x80x9cTopics in Biologyxe2x80x94The Inactivation of Cytochrome P450RAIxe2x80x9d, Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 201-210.
Hanzlik, et al. xe2x80x9cSuicidal Inactivation of Cytochrome P450RAI by Cyclopropylaminesxe2x80x94Evidence for Cation-Radical Intermediatesxe2x80x9d, J. Am. Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052. White et al Proc. Natl. Acad. Sci. USA supra.
The present invention provides several new 8-substituted chroman compounds which act as inhibitors of CP450RAI1 and or of CP450RAI2, or both, and as such potentially provide therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy mammals, including humans, are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the enzyme CP450RAI that catabolizes natural RA, endogenous RA level is elevated to a level where desired therapeutic benefits are attained. The chemical structures of the compounds of the invention are summarized in Formula 1 in the Summary Section of this application for patent. Beyond the references already mentioned above, based on CP450RAI inhibitory activity or chemical structure the following art is of interest as background to the invention.
U.S. Pat. Nos. 6,313,107; 6,303,785, 5,965,606; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; WO 95/04036; EP 0 130,795; DE 3316932; DE 3708060; Eyrolles et al., J. Med. Chem.; (1994), 37 1508, 1517; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356.
The present invention relates to compounds of Formula 1: 
wherein R1 is alkyl having 1 to 6 carbons;
R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons or alkylthio of 1 to 6 carbons;
m is an integer having the values of 0 to 6;
n is an integer having the values of 0 to 2;
o is an integer having the values 0 to 4;
p is an integer having the values 0, 1, or 2;
Y is CHxe2x89xa1Cxe2x80x94, CHxe2x89xa1Cxe2x80x94CH2xe2x80x94; or CH2xe2x95x90CHxe2x80x94;
R is is H, alkyl of 1 to 6 carbons, xe2x80x94CH2OR4, CH2xe2x80x94Oxe2x80x94COR4, or a cation of a pharmaceutically acceptable base, and
R4 is alkyl having 1 to 6 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 for the prevention or treatment of diseases and conditions in mammals, including humans, which diseases or conditions are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism""s naturally occurring retinoic acid. Because the compounds act as inhibitors of the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 in conjunction with retinoic acid or other retinoids, and particularly in conjunction with Vitamin A, or with derivatives of Vitamin A having vitamin A activity. In this regard it is noted that retinoids are useful for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The retinoids are also useful for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. Retinoids can also be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoids include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil(copyright), diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
This invention also relates to a pharmaceutical formulation comprising one or more compounds of Formula 1 in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal, including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, or which are controlled by or responsive to the organism""s native retinoic acid. These formulations can also be co-administered with retinoids and/or Vitamin A to enhance or prolong the effects of medications containing retinoids, Vitamin A or of the organism""s native retinoic acid.
The invention also relates to the methods of using these formulations to treat or alleviate the conditions which were described above as treatable by retinoids, or which are controlled by or responsive to the organism""s native retinoic acid.